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Lansing, Felix [Author]; Mukhametzyanova, Liliya [Author]; Rojo-Romanos, Teresa [Author]; Iwasawa, Kentaro [Author]; Kimura, Masaki [Author]; Paszkowski-Rogacz, Maciej [Author]; Karpinski, Janet [Author]; Grass, Tobias [Author]; Sonntag, Jan [Author]; Schneider, Paul Martin [Author]; Günes, Ceren [Author]; Hoersten, Jenna [Author]; Schmitt, Lukas Theo [Author]; Rodriguez-Muela, Natalia [Author]; Knöfler, Ralf [Author]; Takebe, Takanori [Author]; Buchholz, Frank [Author]

Correction of a Factor VIII genomic inversion with designer-recombinases

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  • Media type: E-Article
  • Title: Correction of a Factor VIII genomic inversion with designer-recombinases
  • Contributor: Lansing, Felix [Author]; Mukhametzyanova, Liliya [Author]; Rojo-Romanos, Teresa [Author]; Iwasawa, Kentaro [Author]; Kimura, Masaki [Author]; Paszkowski-Rogacz, Maciej [Author]; Karpinski, Janet [Author]; Grass, Tobias [Author]; Sonntag, Jan [Author]; Schneider, Paul Martin [Author]; Günes, Ceren [Author]; Hoersten, Jenna [Author]; Schmitt, Lukas Theo [Author]; Rodriguez-Muela, Natalia [Author]; Knöfler, Ralf [Author]; Takebe, Takanori [Author]; Buchholz, Frank [Author]
  • imprint: London: Nature Publishing Group, [2024]
  • Published in: Nature Communications ; 13, (2022)
  • Language: English
  • DOI: 10.1038/s41467-022-28080-7
  • Keywords: Designer-Rekombinasen ; gezielte Genreparatur ; monogenic diseases ; Targeted gene repair ; monogenetische Krankheiten ; designer-recombinases ; Molecular evolution ; Molekulare Evolution
  • Origination:
  • Footnote:
  • Description: Despite advances in nuclease-based genome editing technologies, correcting human disease-causing genomic inversions remains a challenge. Here, we describe the potential use of a recombinase-based system to correct the 140 kb inversion of the F8 gene frequently found in patients diagnosed with severe Hemophilia A. Employing substrate-linked directed molecular evolution, we develop a coupled heterodimeric recombinase system (RecF8) achieving 30% inversion of the target sequence in human tissue culture cells. Transient RecF8 treatment of endothelial cells, differentiated from patient-derived induced pluripotent stem cells (iPSCs) of a hemophilic donor, results in 12% correction of the inversion and restores Factor VIII mRNA expression. In this work, we present designer-recombinases as an efficient and specific means towards treatment of monogenic diseases caused by large gene inversions.
  • Access State: Open Access
  • Rights information: Attribution (CC BY)